DESCRIPTION (Applicant's Abstract): The pathophysiology of migraine, a common disorder causing significant disability and economic burden, is still poorly understood. The development of selective agonists for serotonin (5HT) 1B and 5HT1D receptors (5HT1B/1D agonists) has revolutionized headache treatment. The effectiveness of these medications suggests that understanding their mechanism of action will advance knowledge about the etiology of migraine headache. The general aim of this proposal is to elucidate neural mechanisms that mediate the therapeutic effects of selective 5HT1B/1D agonists. To achieve this goal, a series of anatomical and electrophysiological animal studies are proposed. The experiments will determine the distribution and neurotransmitter co-localization of sensory ganglion cells possessing 5HT1B and 5HT1D receptors through use of immunohistochemistry. The distribution and origin of these receptors to intracranial and extracranial structures will be compared by combining retrograde tracing with immunohistochemistry. Experiments utilizing in vivo extracellular electrophysiological techniques will explore functional correlates of anatomic innervation. The experiments will focus on determining whether intracranial vascular structures posses an innervation that is unique in terms of 5HT1B and/or 5HT1D receptors. A clinical study will test the proposed selectivity of 5HT1B/1D agonists for migraine and cluster headache.